US11447776B2ActiveUtilityA1

Antisense molecules and methods for treating pathologies

76
Assignee: UNIV WESTERN AUSTRALIAPriority: Nov 12, 2009Filed: Aug 13, 2020Granted: Sep 20, 2022
Est. expiryNov 12, 2029(~3.4 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Donald WiltonSue FletcherAbbie AdamsPenny Meloni
C12N 2320/33C12N 2310/351C12N 2310/3233C12N 2310/11C12N 15/111C12N 15/113C12N 2310/3181A61P 21/00C12N 2310/315A61K 48/00C12N 2310/321A61K 31/7105A61P 21/04C12N 2310/3521C12N 2310/31A61K 31/7088
76
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Cited by
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References
36
Claims

Abstract

An antisense molecule capable of binding to a selected target site to induce exon skipping in the dystrophin gene, as set forth in SEQ ID NO: 1 to 59.

Claims

exact text as granted — not AI-modified
The claim defining the invention is as follows: 
     
       1. An antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof. 
     
     
       2. The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       3. The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain. 
     
     
       4. An antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping. 
     
     
       5. The antisense oligonucleotide of  claim 4 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       6. The antisense oligonucleotide of  claim 4 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       7. A pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping. 
     
     
       8. The pharmaceutically acceptable salt of an antisense oligonucleotide of  claim 7 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       9. The pharmaceutically acceptable salt of an antisense oligonucleotide  claim 7 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       10. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       11. The method of  claim 10 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       12. The method of  claim 10 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain. 
     
     
       13. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       14. The method of  claim 13 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       15. The method of  claim 14 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       16. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 exon 9 skipping, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       17. The method of  claim 16 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       18. The method of  claim 16 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       19. A pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier. 
     
     
       20. The pharmaceutical composition of  claim 19 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       21. The pharmaceutical composition of  claim 19 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain. 
     
     
       22. A pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier. 
     
     
       23. The pharmaceutical composition of  claim 22 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       24. The pharmaceutical composition of  claim 22 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       25. A pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier. 
     
     
       26. The pharmaceutical composition of  claim 25 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       27. The pharmaceutical composition of  claim 25 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       28. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       29. The method of  claim 28 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       30. The method of  claim 28 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain. 
     
     
       31. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       32. The method of  claim 31 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       33. The method of  claim 31 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain. 
     
     
       34. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. 
     
     
       35. The method of  claim 34 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. 
     
     
       36. The method of  claim 34 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

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